CN115636766A

CN115636766A - Ceramide clathrate compound eutectic crystal and preparation method and application thereof

Info

Publication number: CN115636766A
Application number: CN202211317780.3A
Authority: CN
Inventors: 黄永焯; 申欢; 刘二刚
Original assignee: Zhongke Zhongshan Pharmaceutical Innovation Research Institute
Current assignee: Zhongke Zhongshan Pharmaceutical Innovation Research Institute
Priority date: 2022-10-26
Filing date: 2022-10-26
Publication date: 2023-01-24
Anticipated expiration: 2042-10-26

Abstract

The invention provides a ceramide inclusion compound eutectic, which comprises a eutectic ligand and a pharmaceutical active ingredient included by the eutectic ligand; the active component of the medicine is ceramide II, and the eutectic ligand is cyclodextrin. The clathrate eutectic crystal formed by the ceramide II and the cyclodextrin has better water solubility, better thermal stability and a more definite crystal structure. In addition, the preparation of the nanoparticles by the fusion solvent injection method and the crystallization by the anti-solvent method can realize the preparation of the inclusion compound eutectic formed by the ceramide II and the cyclodextrin by combining with proper heating temperature, and the preparation method is simple and easy to implement and is convenient to popularize and apply.

Description

Ceramide clathrate compound eutectic crystal and preparation method and application thereof

Technical Field

The invention relates to the field of fine chemical engineering and application, in particular to a ceramide clathrate eutectic and a preparation method and application thereof.

Background

Ceramide is a sphingolipid with biological activity, which is composed of sphingosine and fatty acid, mainly exists on cell membranes, is one of important components of stratum corneum, and also has physiological functions of moisturizing, maintaining skin barrier, resisting aging, resisting allergy, inducing apoptosis and the like. Ceramide is also a common second messenger molecule in apoptosis, is used as an important medium in exogenous and endogenous pathways of apoptosis, plays an important role in regulating various biological activities such as apoptosis, growth, differentiation, stress response and the like, and can participate in the generation and development of cardiovascular and cerebrovascular diseases by regulating lipid metabolism, inflammatory response, vascular endothelial function and the like. Researches report that ceramide can cause damage changes such as enhancement of oxidative stress and increase of apoptosis of liver cells and mediate pathological changes such as liver fibrosis and inflammatory reaction.

From the chemical structure, sphingosine is connected with fatty acid at the amine position to form ceramide. However, ceramide molecules are not unique and refer to a class of molecules, since sphingosine can be composed of different molecules, or different fatty acids can bind to sphingosine. Among them, ceramide II is a dihydroceramide whose N-acyl group is designated as octadecyl (stearoyl), and is extremely poor in water solubility and stability, so that its application is limited. In order to solve the problems of solubility and stability of ceramide, the traditional method is to prepare the ceramide into nano emulsion, liposome, nano particle or nano suspending agent and the like so as to improve the solubility and stability of the ceramide.

Cyclodextrins (CD) are a class of cyclic oligosaccharides produced by starch under the influence of glucosyltransferases, which are typically produced by certain species of the genus Bacillus. The cyclodextrin has a stereo chiral cavity with inner hydrophobic and outer hydrophilic. The inner side of the cavity of the cyclodextrin structure consists of two circles of hydrogen atoms and one circle of oxygen atoms of glycosidic bonds and is under the shielding of C-H bonds, so that the inner cavity of the cyclodextrin is hydrophobic, and the outer side of the cyclodextrin molecule is hydrophilic due to the aggregation of hydroxyl groups. The cyclodextrin is composed of glucose, so the cyclodextrin has the characteristics of no toxicity, no harm, no side effect, capability of being absorbed by human bodies and the like, has the general property of starch, can be used as a filler and a binder of medicaments, and is widely applied in the fields of medicines, foods, chemical industry, materials, environmental protection, analytical chemistry and the like.

Disclosure of Invention

Based on the above, the invention provides a ceramide clathrate eutectic which has better water solubility and better thermal stability, and also has a definite crystal structure.

The invention is realized by the following technical scheme.

A ceramide clathrate co-crystal comprising a co-crystal ligand, and a pharmaceutically active ingredient clathrated by the co-crystal ligand; the active ingredient of the medicine is ceramide II, and the eutectic ligand is cyclodextrin.

In one embodiment, the cyclodextrin is alpha-cyclodextrin.

In one embodiment, the ceramide ii/α cyclodextrin inclusion compound co-crystal has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 θ (°) angles:

5.3 degrees +/-0.2 degrees, 7.3 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 12.8 degrees +/-0.2 degrees, 13.2 degrees +/-0.2 degrees, 16.7 degrees +/-0.2 degrees, 18.3 degrees +/-0.2 degrees, 19.6 degrees +/-0.2 degrees, 22.3 degrees +/-0.2 degrees, 27.4 degrees +/-0.2 degrees and 37.7 degrees +/-0.2 degrees.

In one embodiment, the ceramide ii/α cyclodextrin inclusion compound co-crystal has an X-ray powder diffraction pattern substantially as shown in fig. 5.

In one embodiment, the ceramide II/alpha cyclodextrin inclusion compound co-crystal has a melting point of 317 ℃. + -. 5 ℃.

In one embodiment, in the ceramide clathrate eutectic, the mass percentage of the ceramide II is 18.5% -20.5%.

The invention also provides a preparation method of the ceramide clathrate compound eutectic, which comprises the following steps:

mixing ceramide II with a first solvent to prepare a ceramide solution;

mixing cyclodextrin with water to prepare cyclodextrin water solution;

heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the ceramide solution to prepare a mixed solution;

cooling the mixed solution, standing, and collecting precipitated solid;

wherein the first solvent is a water-miscible organic solvent.

In one embodiment, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.

In one embodiment, the volume ratio of the first solvent to water in the mixed solution is 3 (7-60).

In one embodiment, the molar ratio of the ceramide II to the cyclodextrin in the mixed solution is 1 (1-20).

In one embodiment, the addition of the ceramide solution satisfies one or more of the following conditions:

(1) Controlling the adding time to be 0.5-30 min based on 1-3 mL of the ceramide solution;

(2) Stirring the cyclodextrin water solution at the rotating speed of 100 rpm-1000 rpm.

The invention also provides application of the ceramide clathrate compound eutectic in preparation of chemical preparations, medicines, cosmetics or skin care products.

Compared with the prior art, the ceramide clathrate eutectic disclosed by the invention has the following beneficial effects:

the invention obtains the inclusion compound eutectic formed by ceramide II and cyclodextrin through research and preparation. Compared with the traditional inclusion compound, the inclusion compound eutectic formed by the ceramide II and the cyclodextrin has better water solubility; meanwhile, compared with ceramide II, the melting point of the clathrate compound eutectic is obviously increased, which shows that the thermal stability of the ceramide II/cyclodextrin clathrate compound eutectic is improved. In addition, the clathrate eutectic also has a more definite crystal structure and is hexahedral. Different from the mode of forming crystals by utilizing hydrogen bonds, electrostatic interaction and the like between the active ingredients of the medicaments and the eutectic ligand in the conventional eutectic preparation, the inclusion compound eutectic crystal provided by the invention utilizes the characteristic that cyclodextrin and ceramide II can form an inclusion compound, and the cyclodextrin and the ceramide II are assembled by a host and an object to form the inclusion compound eutectic crystal so as to increase the water solubility of the ceramide II.

Furthermore, the preparation method of the invention is simple and easy to implement, and is convenient for popularization and application.

Drawings

FIG. 1 is a schematic view of a process for preparing a ceramide clathrate co-crystal provided by the invention;

FIG. 2 is an optical microscope photograph of the ceramide clathrate co-crystal provided by the present invention;

FIG. 3 is a H-NMR spectrum of a ceramide II, alpha-cyclodextrin and a ceramide II/alpha-cyclodextrin inclusion compound co-crystal provided by the invention;

FIG. 4 is an infrared spectrum of a ceramide II, alpha-cyclodextrin and a ceramide II/alpha-cyclodextrin inclusion compound co-crystal provided by the present invention;

FIG. 5 is an XPRD spectrum of a ceramide II, alpha-cyclodextrin and a ceramide II/alpha-cyclodextrin inclusion compound co-crystal provided by the present invention (the abscissa is an angle 2 theta (°), and the ordinate is intensity);

FIG. 6 is a DSC chart of the ceramide II, alpha-cyclodextrin and ceramide II/alpha-cyclodextrin inclusion compound co-crystal provided by the present invention (the abscissa is temperature (. Degree. C.) and the ordinate is heat flow rate (W/g)).

Detailed Description

To facilitate an understanding of the invention, the invention will now be described more fully hereinafter with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the invention, "a plurality" means at least two, e.g., two, three, etc., unless explicitly specified otherwise. In the description of the present invention, "a plurality" means at least one, e.g., one, two, etc., unless specifically limited otherwise.

The words "preferably," "more preferably," and the like, in the present disclosure mean embodiments of the disclosure that may, in some instances, provide certain benefits. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.

When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.

All percentages, fractions and ratios are calculated on the total mass of the composition of the invention, unless otherwise indicated. All qualities relating to the listed ingredients are given to the content of active substance, unless otherwise specified, and therefore they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percent content" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless otherwise indicated. All formulations and tests herein occur at 25 ℃ environment, unless otherwise indicated. The use of "including," "comprising," "containing," "having," or other variations thereof herein, is meant to encompass the non-exclusive inclusion, as such terms are not to be construed. The term "comprising" means that other steps and ingredients can be added that do not affect the end result. The compositions and methods/processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any of the additional or optional ingredients, components, steps, or limitations described herein. The terms "potency", "performance", "effect" and "efficacy" are not distinguished from one another herein.

"pharmaceutically acceptable" refers to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to a patient and commensurate with a reasonable benefit/risk ratio.

"pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and/or pharmacological effect, either in vivo or in vitro, and often provides a beneficial effect. The "drug" is not particularly limited in the range that produces physiological and/or pharmacological effects in vivo, and may be systemic or local. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances or an inert substance that does not interact with other substances.

The dosage form and mode of administration of the compound of the present invention or its pharmaceutical composition are not particularly limited.

Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils, or mixtures of these materials. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. If suspensions may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium methoxide and agar, or mixtures of these substances.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalants. Is prepared by mixing the active ingredient under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The invention provides a ceramide inclusion compound eutectic, which comprises a eutectic ligand and a pharmaceutical active ingredient included by the eutectic ligand; the active component of the medicine is ceramide II, and the eutectic ligand is cyclodextrin.

In one particular example, the cyclodextrin is alpha-cyclodextrin.

In a specific example, the X-ray powder diffraction pattern of the ceramide ii/α cyclodextrin inclusion compound co-crystal has characteristic diffraction peaks at the following 2 θ (°) angles:

In a specific example, the X-ray powder diffraction pattern of the ceramide ii/alpha cyclodextrin inclusion compound co-crystal is substantially as shown in fig. 5.

In one particular example, the differential scanning calorimetry curve of the ceramide ii/α cyclodextrin inclusion co-crystal is substantially as shown in fig. 6.

In one specific example, the ceramide II/alpha cyclodextrin inclusion compound co-crystal has a melting point of 317 ℃. + -. 5 ℃.

It is understood that in the present invention, the melting point of the ceramide II/alpha cyclodextrin inclusion co-crystal includes, but is not limited to, 312 ℃, 313 ℃, 314 ℃, 315 ℃, 316 ℃, 317 ℃, 318 ℃, 319 ℃, 320 ℃, 321 ℃, 322 ℃.

In a specific example, the mass percent of the ceramide II in the ceramide clathrate eutectic is 18.5% -20.5%.

It is understood that the mass percentage of ceramide II in the ceramide clathrate eutectic includes, but is not limited to, 18.5%, 18.7%, 18.9%, 19%, 19.2%, 19.4%, 19.6%, 19.8%, 20%, 20.2%, 20.4%, 20.5%.

In one specific example, the ceramide clathrate co-crystal has a well-defined crystal habit, presenting six faces.

With reference to fig. 1, the present invention further provides a preparation method of the ceramide clathrate compound eutectic, which comprises the following steps:

mixing ceramide II with a first solvent to prepare a ceramide solution;

mixing cyclodextrin with water to prepare cyclodextrin water solution;

heating the cyclodextrin water solution to 30-60 ℃, and then adding a ceramide solution to prepare a mixed solution;

cooling the mixed solution, standing, and collecting precipitated solid;

wherein the first solvent is an organic solvent miscible with water.

The first solvent serves as a solvent for the ceramide II, and can serve as a diluent and a transmission medium of the medicament. After the ceramide solution is injected into the aqueous solution of cyclodextrin, the solvent can be rapidly combined with water molecules, so that the dispersion of ceramide II in water and the formation of an inclusion compound eutectic are promoted; on the other hand, the organic solvent can be used as a poor solvent of the cyclodextrin to promote the precipitation of the clathrate eutectic crystal from the solution.

In a specific example, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.

In a specific example, the volume ratio of the first solvent to water in the mixed solution is 3 (7 to 60).

As can be understood, in the present invention, the volume ratio of the first solvent to water in the mixed solution includes, but is not limited to 3:7, 3:8, 3:9, 3.

More specifically, a fixed volume of ceramide solution is injected into the aqueous cyclodextrin solution, and the ratio of organic solvent to water is controlled within a certain range, such as methanol: water = 1; ethanol, water =1, 20-3:7; acetonitrile, water = 1; acetone, water = 1; isopropanol-water = 1; ethylene glycol water =1, 20-3:7, and the above solvent/water ratio range can be complemented with blank solvent when the ceramide solvent is insufficient.

In a specific example, the molar ratio of the ceramide II to the cyclodextrin in the mixed solution is 1 (1-20).

As can be understood, in the present invention, the molar ratio of ceramide ii to cyclodextrin in the mixed solution includes, but is not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1.

In a specific example, the concentration of ceramide II in the ceramide solution is 0.5mg/mL to 20mg/mL.

In a specific example, the concentration of cyclodextrin in the aqueous cyclodextrin solution is 3mg/mL to 80mg/mL. More specifically, in the alpha-cyclodextrin aqueous solution, the concentration of the alpha-cyclodextrin is 3 mg/mL-80 mg/mL. It is understood that, in the present invention, the concentration of the alpha-cyclodextrin in the aqueous alpha-cyclodextrin solution includes, but is not limited to, 3mg/mL, 5mg/mL, 7mg/mL, 10mg/mL, 11mg/mL, 12mg/mL, 13mg/mL, 14mg/mL, 15mg/mL, 16mg/mL, 17mg/mL, 18mg/mL, 19mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL, 80mg/mL. Preferably, the concentration of the alpha-cyclodextrin in the aqueous alpha-cyclodextrin solution is 20mg/mL.

In a specific example, the adding time of the ceramide solution is controlled to be 0.5min to 30min based on 1mL to 3mL of the ceramide solution.

It is understood that, in the present invention, the adding time of the ceramide solution is controlled by, but not limited to, 0.5min, 0.6min, 0.7min, 0.8min, 1min, 1.2min, 1.4min, 1.5min, 1.6min, 1.7min, 1.8min, 1.9min, 2min, 2.1min, 2.2min, 2.3min, 2.4min, 2.5min, 3min, 4min, 5min, 6min, 7min, 8min, 10min, 15min, 20min, 25min, 30min, based on 1mL to 3mL of the ceramide solution. Preferably, the time of addition is controlled to be 3min.

In a specific example, the aqueous cyclodextrin solution is stirred at a speed of 100rpm to 1000rpm during the addition of the ceramide solution.

It is understood that, in the present invention, the rotation speed of stirring the aqueous cyclodextrin solution during the addition of the ceramide solution includes, but is not limited to, 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, 800rpm, 900rpm, 1000rpm.

In one specific example, the mixture is cooled to 4 ℃ to 30 ℃.

In a specific example, the mixture is allowed to stand for 4 to 72 hours.

In a specific example, the method further comprises the following steps after collecting the precipitated solid:

filtering the precipitated solid, washing the solid for 1 to 3 times by using ice water or a precooled crystallization solvent, and collecting a white solid; then the white solid is dried for 1 to 24 hours at the temperature of between 30 and 60 ℃.

The invention also provides application of the ceramide clathrate compound eutectic in preparation of chemical agents, medicines, cosmetics or skin care products.

The invention also provides a composition for treating inflammation, which comprises the ceramide clathrate eutectic crystal and a carrier or an auxiliary material.

The invention also provides a composition for treating cardiovascular and cerebrovascular diseases, which comprises the ceramide clathrate eutectic crystal and a carrier or an auxiliary material.

In a specific example, the carrier or excipient is a pharmaceutically acceptable carrier or pharmaceutically acceptable excipient.

The ceramide clathrate co-crystal and the preparation method thereof according to the present invention will be described in further detail with reference to specific examples below. The starting materials used in the following examples are all commercially available products unless otherwise specified.

Example 1

The embodiment provides a ceramide clathrate compound eutectic, which is prepared by the following specific steps:

(1) Respectively preparing an aqueous solution of alpha-cyclodextrin and a ceramide II solution. Wherein the solvent of the ceramide II is methanol, the concentration of the methanol is 1mg/mL, and the concentration of the alpha-cyclodextrin is 7mg/mL.

(2) Heating the cyclodextrin aqueous solution to 50 deg.C; 1mL of ceramide II solution was poured into 7mL of cyclodextrin aqueous solution with stirring at 100rpm, and the addition time was controlled to 1 minute, and 2mL of methanol was added and stirring was continued for 0.5 minute.

(3) Stopping heating and stirring, and cooling the mixed solution of the ceramide II and the cyclodextrin to 15 ℃; standing for 6 hr until the crystal precipitation is completed.

(4) Filtering to obtain white solid, washing with 4 deg.C water for 3 times; and then drying the product at 40 ℃ for 48 hours to obtain white powder which is an inclusion compound eutectic formed by ceramide II and alpha-cyclodextrin. The yield of the product is 80 percent based on ceramide II.

Comparative example 1

The comparative example provides a preparation method for trying to prepare an alpha-cyclodextrin eutectic crystal, which specifically comprises the following steps:

(1) Preparing an aqueous solution of alpha-cyclodextrin, wherein the concentration of the alpha-cyclodextrin is 7mg/mL.

(2) The aqueous cyclodextrin solution was heated to 50 ℃.

(3) Stopping heating, and cooling the cyclodextrin water solution to 15 ℃; after standing for 6 hours, no solid precipitated.

The ceramide clathrate co-crystal prepared in example 1 is characterized by crystal morphology, H-NMR, infrared spectrum, X-ray powder diffraction (XRD) and Differential Scanning Calorimetry (DSC), and the characterization results are as follows:

(1) Morphology of crystal

The clathrate eutectic prepared in example 1 above was placed on a glass slide, and the morphology of the sample was observed and recorded by a scanning electron microscope, and the results are shown in fig. 2: the eutectic crystal formed by the ceramide II and the alpha-cyclodextrin has definite crystal habit, and particularly, six faces are presented.

(2)H-NMR

Ceramide II, alpha-cyclodextrin and the inclusion compound prepared in example 1 above for co-crystallization d ₆ The hydrogen spectra were determined after the DMSO dissolution, and the results are shown in FIG. 3. The H-NMR data of the co-crystal included signals of both ceramide II and alpha-cyclodextrin, confirming that the crystal consisted of two components.

(3) Infrared spectroscopy

The IR spectra of ceramide II, alpha-cyclodextrin and the inclusion co-crystal prepared in example 1 are shown in FIG. 4. Wherein the characteristic peak of ceramide II is 447cm ^-1 、482cm ^-1 、522cm ^-1 、568cm ^-1 、601cm ^-1 、708cm ^-1 、759cm ^-1 、950cm ^-1 、996cm ^-1 、1021cm ^-1 、1055cm ^-1 、1075cm ^-1 、1151cm ^-1 (ii) a The characteristic peak of cyclodextrin is 400-2000cm ^-1 To (c) to (d); compared with the two, most characteristic peaks related to the ceramide II in the infrared spectrum of the inclusion compound eutectic formed by the ceramide II and the alpha-cyclodextrin disappear, the infrared spectrum of the inclusion compound eutectic is consistent with that of the alpha-cyclodextrin on the whole, and the fact that the drug and the alpha-cyclodextrin form the inclusion compound indicates that the characteristic peaks of the ceramide II in the structure are covered by the cyclodextrin.

(4)XRD

The XPRD patterns of ceramide ii, α -cyclodextrin and the inclusion complex co-crystal prepared in example 1 above are shown in fig. 5. Wherein XRD diffraction peaks of the ceramide II/alpha cyclodextrin eutectic are 5.285 degrees, 7.311 degrees, 10.661 degrees, 12.761 degrees, 13.185 degrees, 16.73 degrees, 18.265 degrees, 19.585 degrees, 22.272 degrees, 27.4 degrees and 37.691 degrees. The characteristic diffraction peak of crystal XPRD is completely different from that of alpha-cyclodextrin, which shows that the crystal is not simple physical mixture but forms a new crystal form, and HNMR results show that the crystal simultaneously contains the alpha-cyclodextrin and ceramide II, so that the crystal can be determined to be ceramide II/alpha-cyclodextrin eutectic.

(5)DSC

The DSC spectra (heating rate by DSC: 10K/min) of the co-crystal of ceramide II and alpha-cyclodextrin and the inclusion compound prepared in example 1 are shown in FIG. 6. The melting point of the ceramide II is 73.1 ℃, after the ceramide II forms a eutectic with alpha-cyclodextrin, the melting point of the clathrate eutectic is 316.6 ℃, and the thermal stability of the ceramide II is obviously improved.

Solubility determination experiments were performed on ceramide ii and the ceramide- α -cyclodextrin inclusion compound co-crystals prepared in example 1, and the results were as follows:

the ceramide II/alpha cyclodextrin inclusion compound co-crystal prepared in example 1 improves the solubility of the drug in water. Ceramide II is almost insoluble in water and has a solubility of less than 1 mu g/mL, while the solubility of the ceramide II/alpha cyclodextrin inclusion compound eutectic in water is about 30 mu g/mL, and the water solubility is obviously increased.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the present invention as set forth in the appended claims. Therefore, the protection scope of the present patent shall be subject to the content of the appended claims, and the description and drawings can be used to explain the content of the claims.

Claims

1. A ceramide clathrate co-crystal comprising a co-crystal ligand, and a pharmaceutically active ingredient included by the co-crystal ligand; the active ingredient of the medicine is ceramide II, and the eutectic ligand is cyclodextrin.

2. The ceramide clathrate co-crystal of claim 1, wherein the cyclodextrin is a-cyclodextrin.

3. The ceramide clathrate co-crystal of claim 2, characterized in that the ceramide ii/a cyclodextrin clathrate co-crystal has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ (°) angles:

4. The ceramide clathrate co-crystal of claim 2, characterized in that ceramide ii/alpha cyclodextrin clathrate co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 5.

5. The ceramide clathrate co-crystal of claim 2, characterized in that the ceramide ii/alpha cyclodextrin clathrate co-crystal has a melting point of 317 ℃ ± 5 ℃.

6. The ceramide clathrate cocrystal of any one of claims 1 to 5, wherein the ceramide II is present in an amount of 18.5 to 20.5% by mass.

7. A method of preparing a ceramide clathrate co-crystal as claimed in any one of claims 1 to 6, comprising the steps of:

mixing ceramide II with a first solvent to prepare a ceramide solution;

mixing cyclodextrin with water to prepare cyclodextrin water solution;

cooling the mixed solution, standing, and collecting precipitated solids;

wherein the first solvent is a water-miscible organic solvent.

8. The method for preparing the ceramide clathrate eutectic crystal as claimed in claim 7, wherein the first solvent is one or more selected from methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol and ethylene glycol.

9. The method for preparing a ceramide clathrate eutectic crystal according to claim 7, characterized in that a volume ratio of the first solvent to water in the mixed solution is 3 (7-60).

10. The method for preparing a ceramide clathrate co-crystal according to claim 7, wherein a molar ratio of the ceramide II to the cyclodextrin in the mixed solution is 1 (1-20).

11. The method of preparing a ceramide clathrate co-crystal as claimed in any one of claims 7 to 10, wherein the ceramide solution is added in one or more of the following conditions:

12. Use of a ceramide clathrate co-crystal according to any one of claims 1 to 6 in the preparation of a chemical, pharmaceutical, cosmetic or skin care product.